Potential Drug Targets for Sepsis Identified

In a study on mice, scientists at The Scripps Research Institute have found new drug targets for sepsis by identifying an important
pathway involving the vascular coagulation system and certain cells in the immune system.

By disrupting this pathway, the scientists could save mice from death due to sepsis.

Although researchers led by Scripps Research Professor Wolfram Ruf and his postdoctoral fellow Frank Niessen, don't guarantee that
this preclinical success will translate into human therapies, they believe that their experiments may perk up the diagnosis of heterogeneous sepsis syndromes and yield potent drugs for treating people who suffer from sepsis.

"We have identified a key connection of signaling pathways in the cascade of events leading to sepsis. This defines a crucial
point where the immune system spirals out of control to cause severe sepsis and where there is an opportunity for therapeutic intervention," Nature quoted the authors, as saying.

The disease sepsis is quite severe, fast moving, dramatic, and often fatal. It is caused due to a violent bacterial infection
that enters the bloodstream. Tythe invasion by these bacteria leads to the production of endotoxins and other toxic chemicals initiating a widespread inflammatory response of the innate immune system.

Scientists have for long being trying many therapeutic approaches for the treatment of sepsis. The sole option for many years was to
give powerful, broad-spectrum antibiotics for controlling the bacterial
infection. But usually, it was too late by the time these were administered.

The second approach to intervention involved the disruption of the connection between coagulation and immunity, and for that
anticoagulants have proven to be an effective treatment in severe sepsis.

Recently, the U.S. Food and Drug Administration (FDA)
approved the use of a recombinant form of activated protein C (Xigris) for the treatment of sepsis, which seemed to yield positive results, in part, by controlling coagulation. But, at the same time other anticoagulants have not been successful in clinical trials and it has been indicate by recent experiments in mice that Xigris guards the vascular endothelium directly through cell signalling, rather than regulating coagulation.

While the coagulation process is a tightly controlled
mechanism meant for preventing blood loss due to injury, but in diseases like Ebola and sepsis it is aberrantly activated. Though the link between coagulation and inflammation is one that scientists have known about for years, the exact molecules that connect coagulation to the inflammatory response in sepsis have remained a mystery.

In order to understand the process, the researchers turned to knockout mice missing signaling receptors for coagulation enzymes, called the protease activated receptors (PARs). They found that mice lacking
PAR1, also known as the thrombin receptor, were less prone to die from sepsis. They made a surprising discovery that when exposed to endotoxin PAR1-deficient animals initially became very sick, but recovered more quickly from systemic inflammation and thus escaped the deadly complication of sepsis syndrome.

This indicated that normal mice could also be rescued from death when they received pharmacological drugs that block the PAR1
receptor or very high doses of coagulation inhibitors. Even when inflammation had already peaked this therapeutic intervention was found to be successful. These experiments gave first clue that can suggest that it is the cell signaling component of the coagulation cascade that leads to severe systemic inflammatory response syndromes.

Unexpectedly, the researchers discovered that
coagulation activates the immune system directly for initiating sepsis
syndrome. Particularly, the dendritic cells of the mouse's immune system have a
pivotal role to play and these cells are disturbed in the lymphatic system,
rather than in the blood stream.

It is the dendritic cells that produce potent
pro-inflammatory cytokines in the lymph nodes during immune reactions. After
sensing the increased coagulation in sepsis, the dendritic cells migrate faster
through the lymphatic system and as a result do not remain inside the lymph
nodes. This leads to a release of inflammatory cytokines and chemical signals
directly into the lymph.

It is known that, all the time lymphatic fluid is
recycled into the blood stream through the thoracic duct. This major lymph
vessel connects to the blood stream immediately before blood enters the lungs.
However, in sepsis, inflammatory mediators in the lymph fluid are thus directly
transferred to one of the most vital organs in the body.

Researchers also found downstream components of the
PAR1 signaling pathway. They used chemical probes provided by the Scripps
Molecular Screening Center, to identify that protease signaling on the
dendritic cells induces the production of sphingosine 1 phosphate (S1P), a
bioactive lipid that activates another G protein-couples receptor, the S1P
receptor 3 (S1P3). It was shown in mice that lacked this receptor, that
dendritic cells may also initiate disseminated intravascular coagulation in
sepsis.

Dendritic cells are caught in an amplification circuit
through the connection between S1P3 and PAR1. That's where they activate
coagulation, and are in turn excited by one of the enzymes in the coagulation
cascade to produce severe systemic inflammation.

It was demonstrated that interrupting the S1P3 and
PAR1 communication not only prevents the spread of inflammation though the
body, but it also limits the inflammatory reaction to a desired location: the
lymph node where the immune system fights microorganisms.

This research gives a new view of sepsis and may also
find potential targets that might refurbish a beneficial inflammatory response
while blocking the fatal results of sepsis.

The results of this study are published in recent online issue of Nature.

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